Advanced cancer patients are often deficient in, and their diets thus supplemented with, thiamine (vitamin B1), which is also a common additive in Western world foods as mammals lack the ability to synthesize thiamine. Thiamine is converted to thiamine pyrophosphate (TPP) which is a necessary cofactor for transketolase, a key enzyme in non-oxidative pentose phosphate pathways which shunt carbon away from glycolytic intermediates and form ribose-5-phosphate for increased nucleic acid biosynthesis. Such pathways are often stimulated in situations of active cell proliferation, such as in tumor cells, where lack of oxygen can stimulate non-oxidative pathways which further deprive cells of reducing compounds (e.g., NADP) required for many normal cellular functions. Transketolase has been postulated to be a useful target for the development of anti-cancer therapies which inhibit nucleic acid biosynthetic pathways.
Reported transketolase inhibitors include oxythiamine, 3-[(2-amino-6-methyl-3-pyridinyl)methyl]-5-(2-hydroxyethyl)-4-methyl thiazolium chloride (N3′PT), and 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methyl 2(3H)-thiazolone chloride (thiamine thiazolone). There is a need to find new transketolase inhibitors, especially TPP-related compounds that are selective inhibitors for transketolase (i.e., which at a selected concentration inhibit transketolase more than other TPP-utilizing enzymes).